1. Field of the Invention
The present invention is directed to a method for treating the metabolic syndrome, obesity, prediabetes or metabolic conditions thereof, or Type 2 diabetes, and more particularly to a method for treating the metabolic syndrome, obesity, prediabetes or metabolic conditions thereof, or Type 2 diabetes by administering to a patient a pharmaceutical composition that increases the ratio of dopaminergic neuronal to noradrenergic neuronal activity within the central nervous system, particularly the hypothalamus of the central nervous system of the patient.
The global health crisis of obesity, diabetes and related metabolic disorders has been well established before the turn of this 21st century. The prevalence of each of type 2 diabetes, obesity, pre-diabetes, and metabolic syndrome is reaching pandemic proportions world-wide and their prevalence is expected to continue to rise in the next two decades further exacerbating the current world wide health crisis surrounding these diseases as estimates of people diagnosed with diabetes will likely exceed 350 million globally by 2030 (Wild S, Diabetes Care, 2004, 27:1047). Diabetes and its associated co-morbidity continue to exact an exceptionally high toll on both patients and the healthcare system. In the United States, diabetes represents 11% of the US health care expenditure with cardiovascular disease accounting for approximately 20% of the annual direct medical costs for diabetes (www.diabetes.org). Despite the concerted effort to reduce cardiovascular risk factors in patients with diabetes, sixty-five percent of patients with diabetes will die from heart disease and stroke and the fact remains that type 2 diabetes increases the risk for cardiovascular disease two fold for men and three fold for women relative to gender matched individuals without type 2 diabetes (Conroy, Eur Heart J, 2003, 24: 987). The prevalence of obesity, pre-diabetes and metabolic syndrome each are also increasing world-wide with population estimates that at least double the prevalence of type 2 diabetes and each of these metabolic disorders carries a risk for cardiovascular disease, the leading cause of death in the world (Francischetti E A et al, Int J Clin Pract, 2007, 61:269; Grundy S M, Arterioscler Thromb Vasc Biol 2008, 28:629; Stein P K et al, Diabet Med 2007, 24:855). It is patently obvious that a safe and effective treatment for any and particularly all of these disorders would impart unparalleled significant benefit to humanity and that any prospect for the development of such a global therapy would be the focus of intense research and development by the healthcare industry and academia world-wide for this very reason. This invention provides a new and previously unrecognized paradigm that fills a void for the successful management of these metabolic disorders.
2. Brief Description of the Art
Obesity (commonly defined as a Body Mass Index of approximately >30 kg/m2) is often associated with a variety of pathologic conditions such as hyperinsulinemia, insulin resistance, diabetes, hypertension, and dyslipidemia. Each of these conditions contributes to the risk of cardiovascular disease.
Along with insulin resistance, hypertension, and dyslipidemia, obesity is considered to be a component of the Metabolic Syndrome (also known as Syndrome X) which together synergize to potentiate cardiovascular disease. More recently, the U.S. National Cholesterol Education Program has classified Metabolic Syndrome as meeting three out of the following five criteria: fasting glucose level of at least 110 mg/dl, plasma triglyceride level of at least 150 mg/dl (hypertriglycerdemia), HDL cholesterol below 40 mg/dl in men or below 50 mg/dl in women, blood pressure at least 130/85 mm Hg (hypertension), and central obesity, with central obesity being defined as abdominal waist circumference greater than 40 inches for men and greater than 35 inches for women. The American Diabetes Association estimates that 1 in every 5 overweight people suffer from Metabolic Syndrome.
According to the guidelines of the American Diabetes Association, to be diagnosed with Type 2 diabetes, an individual must have a fasting plasma glucose level greater than or equal to 126 mg/dl or a 2-hour oral glucose tolerance test (OGTT) plasma glucose value of greater than or equal to 200 mg/dl (Diabetes Care, 26:S5-S20, 2003). A related condition called pre-diabetes is defined as having a fasting glucose level of greater than 100 mg/dl but less than 126 mg/dl or a 2-hour OGTT plasma glucose level of greater than 140 mg/dl but less than 200 mg/dl. Mounting evidence suggests that the pre-diabetes condition may be a risk factor for developing cardiovascular disease (Diabetes Care 26:2910-2914, 2003). Prediabetes, also referred to as impaired glucose tolerance or impaired fasting glucose is a major risk factor for the development of type 2 diabetes mellitus, cardiovascular disease and mortality. Much focus has been given to developing therapeutic interventions that prevent the development of type 2 diabetes by effectively treating prediabetes (Pharmacotherapy, 24:362-71, 2004).
Metabolic Syndrome (MS), also referred to as Syndrome X, is another metabolic disorder that affects other pathways and systems in the body. Originally, Metabolic Syndrome was defined as a cluster of metabolic disorders (including obesity, insulin resistance, hypertension, and dyslipidemia primarily hypertriglyceridemia), that synergize to potentiate cardiovascular disease. More recently (2001), the U.S. National Cholesterol Education Program (NCEP) has classified Metabolic Syndrome as meeting any three out of the following five criteria: fasting glucose level of at least 110 mg/dl, plasma triglyceride level of at least 150 mg/dl (hypertriglycerdemia), HDL cholesterol below 40 mg/dl in men or below 50 mg/dl in women, blood pressure at least 130/85 mm Hg (hypertension), and central obesity, with central obesity being defined as abdominal waist circumference greater than 40 inches for men and greater than 35 inches for women. Presently, there are three other internationally recognized definitions for Metabolic Syndrome as follows: 1) World Health Organization 2) American Heart Association/National Heart, Lung and blood Institute (AHA/NHLBI) and 3) International Diabetes Federation (IDF). The definitions of Metabolic Syndrome by the WHO, AHA/NHLBI and IDF are very similar to the definition of the NECP and all use the same metabolic parameters to define the syndrome, but the WHO also includes assessment of insulin fasting insulin levels (Moebus S et al, Cardiovascular Diabetology, 6: 1-10, 2007; Athyros V G et al, Int. J. Cardiology, 117: 204-210, 2007). Yet subtle differences in the thresholds for these metabolic parameters required to be classified as having the syndrome among these different definitions can result in different classification of a particular subject as having or not having the syndrome according to these different definitions. Also, the prevalence of cardiovascular disease (CVD) with MS varies by the definition used. (Moebus S et al, Cardiovascular Diabetology, 6: 1-10, 2007; Athyros V G et al, Int. J. Cardiology, 117: 204-210, 2007). Notably, none of these widely utilized definitions of MS employs vascular pro-inflammatory state, pro-coagulative state, pro-oxidant state, or endothelial dysfunction to define the syndrome. However, these non-metabolic biochemical derangements are often associated with MS. A more recent term for MS plus blood vessel pathophysiology (described just above) has been termed cardiometabolic risk. The American Diabetes Association estimates that 1 in every 5 overweight people suffer from Metabolic Syndrome.
While these disorders and diseases are related, it is clear that they have individual and distinct pathologies. For that reason, drugs used to treat one disorder (type 2 diabetes) may not be effective against another disorder (metabolic syndrome). For instance, drugs that are effective in treating Type 2 diabetes or pre-diabetes have little to no effect on effectively and safely treating Metabolic Syndrome. Additionally, certain drugs used to treat Type 2 diabetes or pre-diabetes may increase blood pressure (hypertension) or cause weight gain in the individuals taking the medication. For example, thiazolidinediones used in the treatment of Type 2 diabetes cause weight gain and has marginal effects on hypertension. Another anti-diabetic agent, metformin, also has marginal effects on hypertension and hypertriglyceridemia. Insulin, which is a hormone used to treat Type 2 diabetes can potentiate hypertension and weight gain. Moreover, anti-hypertensive drugs do not necessarily treat dyslipidemia or obesity, and many can worsen insulin sensitivity instead of improving it. It is therefore not a forgone conclusion that since a drug is an effective anti-diabetes agent, that it will be an effective treatment for metabolic and/or non-metabolic pathologies of metabolic syndrome. Since people with metabolic syndrome do not have existing disease but have a biology that portends ensuing disease, the criteria for safety are also much higher when considering a pharmaceutical agent for the treatment of this syndrome.
Since the Metabolic Syndrome is diagnosed as having several criteria (as described above) yet also encompasses vascular abnormalities such as endothelial dysfunction, vascular pro-inflammatory condition, and vascular pro-coagulative condition, the treatment of Metabolic Syndrome according to the present invention further includes                a. Treatment of endothelial dysfunction associated with cardiovascular disease;        b. Treatment of hypertension, vascular pro-inflammatory state, and pro-coagulative state simultaneously. Examples of pro-inflammatory state blood markers include but are not limited to: C-reactive protein, serum amyloid A protein, interleukin-6, interleukin-1, Tumor Necrosis Factor-alpha, homocysteine, and white blood cell count. Examples of pro-coagulative state blood markers include but are not limited to: hematocrit viscosity, red cell aggregation, plasminogen activator inhibitor-1, fibrinogen, van Willebrand factor, Factor VII, Factor VIII, and Factor IX;        c. Treatment of at least two of hypertension, vascular pro-inflammatory state, or pro-coagulative state simultaneously; and        d. Treatment of at least one of hypertension, vascular pro-inflammatory state, or pro-coagulative state.        
The endothelium can modify circulating factors as well as synthesize and release factors that influence cardiovascular health and disease. Endothelium dysfunction is characterized by alterations in endothelium modulation of the vasculature that favor or potentiate vasoconstriction, a pro-coagulant state, and/or a pro-inflammatory state as well as other biochemical process that all contribute to the initiation and progression of atherosclerosis (Am. J. Cardiol. 91(12A): 3H-11H, 2003; Am. J, Cardiol. 115 Suppl 8A:99S-106S, 2003) or arteriosclerosis (Nigam A et al, Am. J. Cardiol. 92: 395-399, 2003; Cohn J N et al, Hypertension 46:217-220, 2005; Gilani M et al, J. Am. Soc. Hypertens 2007).
A significant complicating issue in the treatment of metabolic disorders is that the individual pathologies of Metabolic Syndrome differ in their nature and magnitude whether presented alone or as part of the syndrome because the pathologies of the syndrome tend to synergize to produce increased risk of morbidity and mortality (Reviewed in G M Reaven, Diabetes, Obesity, and Metabolism, 4: (Suppl. 1) S13-S-18, 2002). In other words, a Metabolic Syndrome subject carries a different increased risk of cardiovascular disease as a result of his/her hypertension than does a hypertensive subject without Metabolic Syndrome. Currently, the U.S. Food and Drug Administration has not approved the use of any drug for the treatment of Metabolic Syndrome. The current definition of Metabolic Syndrome by the NCEP other definitions as described above relates to metabolic derangements and does not include aspects of non-metabolic biochemical pathology associated with the Syndrome such as pro-coagulative state, pro-inflammatory state, pro-oxidant state, or endothelial dysfunction. Yet these non-metabolic biochemical derangements contribute significantly to cardiovascular disease by mechanisms that do not necessarily involve lipid deposition and its attendant consequences of plaque formation in the intimal and inner media vessel walls (i.e., atherosclerosis). Rather, these non-metabolic biochemical abnormalities can potentiate a process that leads to a different type of vascular damage termed arteriosclerosis (defined as thickening and stiffening of the vessel wall) that can have devastating consequences on vascular health and potentiate vascular disease such as large vessel damage, myocardial infarction, stroke, and peripheral vascular disease (Safar M E Frohlich E D (eds) Atherosclerosis, Large Arteries and Cardiovascular Risk. McEniery C M et al, Adv. Cardiol. Basel, Karger, vol. 44, pp. 160-172; Laurent S et al, Eur. Heart J., 27: 2588-2605, 2006). These non-metabolic biochemical pathologies predispose the individual to increased stiffening of the vessel wall by changing the biochemical structure and architecture within the cellular layers of the wall (i.e., extracellular matrix components such as collagen and elastin, etc.) and by changing the contractile state of the smooth muscle cells therein (Safar M E Frohlich E D (eds) Atherosclerosis, Large Arteries and Cardiovascular Risk. McEniery C M et al, Adv. Cardiol. Basel, Karger, vol. 44, pp. 160-172). Such changes can effectuate vascular damage often in a much shorter time frame than those metabolic derangements of Metabolic Syndrome predisposing to atherosclerosis. Moreover, these non-metabolic derangements can be additive to those metabolic disturbances defining the Metabolic Syndrome to exacerbate vascular disease. And, arteriosclerosis can predispose one to atherosclerosis (XX). Since arteriosclerosis often precedes and potentiates atherosclerosis, the ability to successfully treat arteriosclerosis or biochemical events leading to arteriosclerosis, on e may be able to intervene medically at an earlier time point in the chronology of CVSD and produce better clinical outcomes for the patient in the long term.
The mechanisms involving non-metabolic biochemical derangements of a vascular pro-inflammatory state, pro-oxidant state, pro-coagulative state, and endothelial dysfunction to precipitate arteriosclerosis and CVD are exceedingly complex and reviewed in much detail in Nigam A et al, Am. J. Cardiol. 92: 395-399, 2003; Cohn J N et al, Hypertension 46:217-220, 2005; and Gilani M et al, J. Am. Soc. Hypertens 2007.
Previous studies have described the utility of the dopamine agonist, bromocriptine to treat individual pathologies of insulin resistance, hypertension, hypertriglyceridemia and also to treat lipid plaques of atherosclerosis (Meier A H et al, Diabetes Reviews, 4: 464, 1996; U.S. Pat. Nos. 5,006,526 and 5,565,454). However, to our knowledge no literature are available describing the utility of bromocriptine or dopamine agonists to simultaneously treat metabolic derangements of MS and non-metabolic derangements associated with MS or to simultaneously treat several non-metabolic derangements associated with MS or to treat arteriosclerosis (as opposed to atherosclerosis) or to reduce actual adverse cardiovascular events such as myocardial infarction or stroke or peripheral vascular disease. Moreover, although timing of administration to effectuate improvements in metabolic derangements such as type 2 diabetes and insulin resistance has been described (U.S. Pat. Nos. 6,004,972; 5,866,584; 5,756,513; and 5,468,755), such import of circadian timing to maximize the benefit of dopamine agonist therapy upon non-metabolic biochemical activities predisposing to arteriosclerosis and CVD that are wholly different from those metabolic influences as previously described in the literature, have not been delineated. In fact, the available literature indicate that dopamine agonist therapy such as bromocriptine is associated with increased adverse cardiovascular events such as myocardial infarction, stroke, and cerebrovascular accident (Ruch A et al, Obstet Gynecol 74: 448-451, 1989; Iffy L et al, Med Law 15: 127-134, 1996; Katz M et al, Obstet Gynecol 66: 822-824, 1985; Iffy et al, Am J Ther 5: 111-115, 1998; Ddutt S et al, Aust N Z J Obstet Gynaecol 38: 116-117, 1998). In fact, the effect of dopamine agonists such as bromocriptine to increase these adverse cardiovascular events was serious enough for the U.S. Food and Drug Administration to place a warning on the labels for these pharmaceutical dopamine agonists stating that their use has been associated with increases in hypertension, stroke, cerebrovascular accidents, and myocardial infarction (Physicians Desk Reference, Parlodel Package Insert). In stark contradistinction to this described relationship between increased dopamine agonist exposure and increased vascular disease, the current invention demonstrates that if the dopamine agonist therapy is used at the appropriate dosage and at the appropriate time of day so that its levels are not elevated throughout a greater portion of the day but are confined to a discrete daily interval of the day that approximates the natural daily circadian peak of central nervous system dopaminergic activity in healthy individuals without either vascular disease or increased levels of metabolic or non-metabolic biomarkers of vascular disease and given to a subject in need of treatment for cardiovascular disease, then dopamine agonist therapy actually decreases vascular disease and adverse vascular events, not increases them. Such daily timing of dopamine agonist within the present invention to improve arteriosclerosis biomarkers, arteriosclerosis, and CVD events also is at a time of day to reduce exaggerated increases in central noradrenergic tone that potentiate these vascular disorders. And, these beneficial vascular effects of timed dopamine agonist therapy are not the result of influences to markedly reduce hyperglycemia, plasma triglyceride levels, or blood pressure (see examples below).
The vascular endothelium is a dynamic tissue, responding to the humoral milieu it is bathed in to impact vascular architecture, and blood vessel contractile tone. Endothelial dysfunction may be defined as a biochemical state wherein the endothelium potentiates vasoconstriction, inflammation of the vessel wall intima and media layers, and physical restructuring of the extracellular matrix of the vessel wall to potentiate wall thickening and stiffening. Among the humoral factors known to stimulate biochemical endothelial dysfunction, increases in pro-inflammatory factors such as monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNFalpha), interleukin-6 (IL-6) and C-reactive protein (CRP) all stimulate endothelial changes that facilitate inflammation at the vessel wall that in turn potentiate vessel wall stiffening. Moreover, decreases in plasma adiponectin, an anti-inflammatory factor at the vessel wall, also facilitate endothelial dysfunction and inflammation at the endothelium thereby potentiating vessel wall stiffening (i.e., arteriosclerosis). Vascular inflammation is coupled to and facilitates arterial stiffness (Yasmin M C et al, Arterioscler. Thromb. Vasc. Biol. 24: 969-974, 2004; Duprez D A et al, J. Hum. Hypertens. 19: 515-519, 2005; Booth A et al, Arthritis Rheum. 50: 581-588, 2004).
Vascular oxidative stress can also contribute to arterial wall stiffness. Increases in oxidative stress that produce reactive oxygen species (ROS) can scavenge nitric oxide, a potent endothelium stimulus for vasodilatation and normal endothelium function. Reduced vascular nitric oxide (NO) availability can potentiate arterial wall stiffness and a direct correlation between arterial stiffness and endothelial function has been observed in both the coronary and peripheral circulations (Wilkinson I B et al, Circulation 105: 213-217, 2002; Schmitt M et al, Hypertension 46: 227-231, 2005; Ichigi Y et al, J. Am. Coll. Cardiol. 45: 1461-1466, 2005; Ceravolo R et al, J. Am. Coll. Cardiol. 41: 1753-1758, 2003). Endothelial dysfunction and reduced NO availability can derive from too little NO synthase activity or from a consequence of over-active but “uncoupled” NO synthase activity. Paradoxically, vascular NO synthase expression may be increased in states of endothelial dysfunction and vascular disease. In the consequence of increased uncoupled vascular NO synthase activity, the enzyme functions to generate increased ROS and protein tyrosine nitration in the vessel wall while reducing the amount of available NO that collectively potentiate vascular arterioscleosis (Upmacis R K et al, Am. J. Physiol. 293: H2878-2887, 2007; Ginnan R et al, Free Radic. Biol. Med., Jan. 22, 2008; Landmesser et al, J. Clin. Invest., 111: 1201-1209, 2003; Munzel T et al, Arterioscler. Thromb. Vasc. Biol., 25: 1551-1557, 2005). Beyond their influence on inflammation, the above described adipokines (increased TNFalpha and MCP-1 and decreased adiponectin) and increased CRP, also may potentiate increases in ROS and protein nitration via perturbations of endothelial function and NO synthase (Rong L et al, Am. J. Physiol. 293: E1703-E1708, 2007; De Keulenger G W et al, Biochem. J. 329: 653-657, 1998). Increases in vessel endothelial NO synthase (eNOS) (Kagota S et al, Life Sciences 78:1187-1196, 2006) and inducible NO synthase (iNOS) are observed in older SHR rats that have increased arterial stiffness (Safar M E, In: Swales J D ed., Textbook of Hypertension, London UK: Blackwell Scientific; 1994:85-102). In the case of increased “uncoupled” NO synthase activity, the uncoupled NO synthase actually produces increased local amounts of superoxide while reducing its NO production thereby contributing to arteriosclerosis and this occurrence appears to be particularly accentuated in diabetes (Alp N J et al, J. Clin. Invest. 112: 725-735, 2003) and may contribute significantly to the arteriosclerosis of diabetes and the consequent increase in cardiovascular events (MI, stroke, and peripheral vascular damage) of diabetes versus non-diabetes subjects. A key hallmark of eNOS uncoupling is an increase in eNOS level or activity with a concurrent decrease in soluble guanyl cyclase level or activity in the endothelium as this enzyme is activated by NO to induce NO beneficial effects on the vasculature.
A pro-coagulative state also can predispose one to increased cardiovascular events. Respecting acute coronary syndrome, acute myocardial infarction, and thrombotic stroke, a critical player in their genesis is a pro-coagulative state, a condition potentiating an increase in the balance between blood clot formation and blood clot dissolution favoring blood clot formation. A pro-coagulative state involves many biochemical factors within the physiology of the body and increases in factors that potentiate blood clot formation and/or inhibit blood clot dissolution can function not only to precipitate an acute CVD event, but also can function to facilitate mechanisms involved in arteriosclerosis as well. Endothelin-1, is an example of such a factor. Endothelin-1 is an endothelium derived factor that is very pro-coagulative and that also functions as a potent vasoconstrictor that can potentiate endothelial dysfunction (Halim A et al, Thromb REs 72: 203-209, 1993; Iwamoto T et al, Nephron 73: 273-279, 1996) and thereby lead to arterial stiffness. Various factors in clot formation such as reactive platelets, plasminogen activator inhibitor-1, and fibrinogen, synergize to alter the endothelium and vessel wall in chronic hyper-coagulative states that can lead to vessel wall restructuring, chronic vasoconstriction and arteriosclerosis.
Endothelial dysfunction as described above may be defined as a biochemical state wherein the endothelium potentiates vasoconstriction, inflammation of the blood vessel wall intima and media layers, and physical restructuring of the extracellular matrix of the blood vessel wall to potentiate wall thickening and stiffening. As such, endothelial dysfunction as defined herein is a potent contributor to arterioscleosis and CVD (Nigam A et al, Am. J. Cardiol. 92: 395-399, 2003; Cohn J N et al, Hypertension 46:217-220, 2005; Gilani M et al, J. Am. Soc. Hypertens 2007). This is an important distinction because those biochemical derangements that affect arteriosclerosis versus atherosclerosis will have distinct beneficial impacts on CVD outcomes. Arteriosclerosis is often a very early sign of later CVD events long before any atherosclerosis is detectable (Nigam A et al, Am. J. Cardiol. 92: 395-399, 2003; Cohn J N et al, Hypertension 46:217-220, 2005; Gilani M et al, J. Am. Soc. Hypertens 2007). Therefore it may be possible to prophylacticly treat one with signs of arteriosclerosis such as endothelial dysfunction, a pro-inflammatory state, a pro-coagulative state, or a pro-oxidant state, which are all easily assessable clinically, in an effort to best prevent the onset of CVD by attacking the problem at its earliest warning signs. There are several simple tests to measure endothelial dysfunction, a vascular pro-inflammatory state, a pro-coagulative state, and a pro-oxidant state. Also, there are several available test to assess presence and degree of arteriosclerosis. It is also true that certain other biochemical derangements within the endothelium may also predispose one to atherosclerosis, however, as it relates to this invention, and as it is defined herein, endothelial dysfunction is a factor that potentiates arteriosclerosis. It can be appreciated that endothelial dysfunction will be characterized by biochemical derangements including but not limited to increased “uncoupled” inducible NO synthase, “uncoupled” endothelial NO synthase, increased ROS, increased production of and exposure to vasoconstrictive factors such as Endothelin-1, and increased pro-inflammatory and pro-coagulative factors.
The metabolic derangements that define the metabolic syndrome as described above differ in their impact on CVD from the non-metabolic derangements described above. Statins, drugs that reduce total and low-density lipoprotein (LDL) cholesterol synthesis by inhibiting HMG-CoA reductase activity and fibrates that reduce plasma triglyceride levels have been shown to reduce blood vessel plaques and CVD events (Colhoun H et al, Lancet 364; 685-696, 2004). Also, anti-hypertensive medications have been shown to reduce CVD events (Sever P et al, Lancet 361: 1149-1158, 2003). However, cardiovascular disease still remains the leading cause of morbidity in the world today and in subjects with type 2 diabetes cardiovascular disease is the leading cause of death. Moreover, in this diabetes patient population, CVD events have been increasing in recent years despite the availability of statins, fibrates and anti-hypertensive medications (Roglic G et al, Diabetes Care, 28: 2130-2135, 2005). Clearly these medications are not completely effective and new methods of preventing CVD and treating CVD are needed. Particularly, an effective treatment for the metabolic pathologies of metabolic syndrome and non-metabolic pathologies associated with metabolic syndrome to effectuate a prevention of, improvement in, reduction of the progression of, or regression of arteriosclerosis and CVD is needed. Methods that reduce arteriosclerosis as well as atherosclerosis and biological potentiators of both these vascular disorders are also needed. Moreover, these methods are particularly needed in subjects with type 2 diabetes. The present invention is believed to be an answer to these needs. A variety of treatments are available for Metabolic Syndrome, obesity, Type 2 Diabetes, and pre-diabetes and related disorders. For example, U.S. Pat. No. 6,506,799 discloses methods of treating cardiovascular diseases, dyslipidemia, dyslipoproteinemia, and hypertension comprising administering a composition comprising an ether compound.
U.S. Pat. No. 6,441,036 discloses fatty acid analogous which can be used for the treatment and/or prevention of obesity, fatty liver and hypertension.
U.S. Pat. No. 6,410,339 discloses use of cortisol agonist for preparing a system for diagnosis of the Metabolic Syndrome and related conditions as belly fatness, insulin resistance including increased risk of developing senile diabetes, i.e., diabetes type II, high blood fats and high blood pressure, in which system the dose of cortisol agonist is in an interval where a difference is obtained in the inhibitory effect of the autoproduction of cortisol in individuals suffering from the Metabolic Syndrome, compared to normal values.
U.S. Pat. No. 6,376,464 discloses peptides and peptide analogues that mimic the structural and pharmacological properties of human ApoA-I. The peptides and peptide analogues are useful to treat a variety of disorders associated with dyslipidemia.
U.S. Pat. No. 6,322,976 discloses, among other things, methods of diagnosing a disease associated with a defect in insulin action, glucose metabolism, fatty acid metabolism, and/or catecholamine action by detecting a mutation in the CD36 gene.
U.S. Pat. No. 6,197,765 discloses a treatment for metabolic syndrome (syndrome-X), and resulting complications, by administration of diazoxide.
U.S. Pat. No. 6,166,017 discloses a method for the medical treatment of diabetes mellitus type II and for counteracting the risk factors forming part of the Metabolic syndrome by administration of ketoconazole.
U.S. Pat. No. 6,040,292 discloses methods for the treatment of diabetes mellitus, including type I, type II, and insulin resistant diabetes (both type I and type II). The methods of the invention employ administration of rhIGF-I/IGFBP-3 complex to a subject suffering from the symptoms of diabetes mellitus. Administration of rhIGF-I/IGFBP-3 to a subject suffering from the symptoms of diabetes mellitus results in amelioration or stabilization of the symptoms of diabetes.
U.S. Pat. No. 5,877,183 discloses methods for the regulation and modification of lipid and glucose metabolism, but not metabolic syndrome, by administering to a subject a dopamine D1 agonist, optionally in combination with a dopamine D2 agonist, an alpha-1 adrenergic antagonist, an alpha-2 adrenergic agonist, or a serotonergic inhibitor, or optionally in combination with a dopamine D2 agonist coadministered with at least one of alpha-1 adrenergic antagonist, an alpha-2 adrenergic agonist, or a serotonergic inhibitor, and further administering the subject a serotonin 5HT1b agonist. It is well known that dopamine agonists function to both activate and deactivate dopamine receptors and thereby reduce dopaminergic neuronal activity.
U.S. Pat. No. 5,741,503 discloses methods for regulating or ameliorating lipid metabolism which comprise administration or timed administration of inhibitors of dopamine beta hydroxylase (DBH). However, the focus of this technology is reduction in noradrenergic activity level only and does not increase dopaminergic neuronal activity inasmuch as DBH is not present in dopaminergic neurons that are anatomically distinct from noradrenergic neurons where DBH resides.
In addition, several U.S. patents disclose use of dopamine agonists such as bromocriptine for use in treating pathologies relating to Type II diabetes. See, for example, U.S. Pat. Nos. 6,855,707, 6,004,972; 5,866,584; 5,756,513; and 5,468,755. Also, bromocriptine has been employed to treat type 2 diabetes or insulin resistance (Pijl H, et al Diabetes Care, 23:1154, 2000; Meier A H et al, Diabetes Reviews, 4: 464, 1996). However, dopamine agonists such as bromocriptine that are dopamine D2 receptor agonists are capable of stimulating pre-synaptic and post-synaptic dopamine receptors. Stimulation of pre-synaptic dopamine receptors with dopamine D2 receptor agonists such as bromocriptine results in marked decreased dopamine release and decreased post-synaptic dopamine binding and activity (i.e., decreased dopaminergic neuronal activity as defined herein) that is the opposite of the effect of dopamine D2 receptor agonist binding to post-synaptic dopamine receptors. Therefore, it was uncertain for some time of how bromocriptine is actually working to improve insulin resistance via interactions with dopamine receptors (i.e., it could not definitively be ascertained if it is the increasing or decreasing dopaminergic neuronal activity that is primarily responsible for the elicitation of its effects). No data were available that definitively answered the question of how bromocriptine, acting as a dopamine agonist, impacted overall dopaminergic neuronal activity. Moreover, it has been demonstrated in the scientific literature that dopamine receptor agonists are capable of improving metabolic disease (Cincotta A H et al, Exp Opin Invest Drugs, 1999, 10:1683) and worsening metabolic disease (Americ S P et al, J Pharmacol Exp Ther, 1984, 228:551; Schmidt M J et al, Eur J Pharmacol, 1983, 90:169; Mohamed H F et al, Life Sci, 1985, 36:731; Durant S, Rev Diabet Stud, 2007, 4:185; e1-Denshart et al, Life Sci, 1987, 40:1531). Likewise, dopamine receptor antagonists have been shown to improve and worsen metabolic disorders (Hajnal et al, Neuroscience, 2007, 148:584; Baptista T et al, Brain Res, 2002, 957: 144) and drugs that lower synaptic dopamine such as rimonabant reduce obesity and dysglycemia (Wright S H et al, Curr Atheroscler Rep, 2008, 10:71). Respecting body weight, dopamine receptor agonists and antagonists both have been employed to reduce feeding and dopamine ligand-receptor binding is associated with both stimulation and inhibition of feeding in different areas of the brain (Hajnal et al, Neuroscience, 2007, 148:584; Szczypka M S et al, Nat Genet, 2000, 25:102; Roseberry A G et al, J NeuroSci, 2007, 27: 7021). Dopamine agonist-receptor binding has also been coupled to increases in blood glucose level and decreases in blood glucose level (Cincotta A H et al, Exp Opin Invest Drugs, 1999, 10:1683; Americ S P et al, J Pharmacol Exp Ther, 1984, 228:551; Schmidt M J et al, Eur J Pharmacol, 1983, 90:169; Mohamed H F et al, Life Sci, 1985, 36:731; Durant S, Rev Diabet Stud, 2007, 4:185). Clearly our understanding of dopamine neurochemistry and neurophysiology involved in the regulation of fuel metabolism has been incomplete and in need of improvement. Moreover, dopamine receptor binding particularly post-synaptic dopamine D1 and D2 receptor agonist binding to their respective receptor sites is susceptible to ligand-induced desensitization (loss of ligand-receptor induced signal transduction and post-synaptic cellular effect such as effect on neuronal action potential or neurotransmitter release), compensation (post-synaptic dopamine receptor number reduction or down-regulation), and counteraction (loss of post-synaptic ligand-receptor effect and/or in certain cases reduction of endogenous neurotransmitter [i.e., dopamine] in the synapse by any means). (Ng G Y et al, Eur J Pharmacol, 1994, 267:7; Lin C W, J Pharmacol Exp Ther, 1996, 276:1022; Ng G Y et al, Proc Natl Acad Sci U.S.A., 1995, 92:10157; So C H et al, Mol Pharmacol, 2007, 72: 450; Ariano M A, Synapse, 1997, 27: 313; Namkung Y et al, J Biol Chem, 2004, 279: 49533; Amar S et al, Int J Nueropsychopharmacol, 2008, 11: 197; Morris S J et al, Eur J Pharmacol, 2007, 577: 44; Cho D I et al, Biochem Biophy Res Commun, 2006, 350: 634; Kim K M et al, J Biol Chem, 2001, 276: 37409; Barton A C et al, Mol Pharmacol, 1991, 39: 650). Dopamine D2 receptor agonists cause a reduction in synaptic dopamine level as evidenced by reductions in dopamine metabolites, DOPAC and HVA (Feenstra M G et al, Naunyn Schmiedebergs Arch Pharmacol, 1983, 324: 108; Pagliari R et al, J Neural Transm Gen Sct, 1995, 101: 13; Kendler K S et al, Life Sci, 1982, 30: 2063) and this effect, in and of itself, is counter to the intent of this invention. Desensitization and/or counteraction preclude effectiveness of dopamine agonists to produce maximized long-term increased dopamine neuronal activity with their sustained use. For example, it has been shown that treatment of subjects with type 2 diabetes for sustained periods of time with the dopamine D2 receptor agonist, bromocriptine, can result in a loss of the maximum anti-diabetes effect of such treatment over time relative to the baseline glycemic control level for these treated subjects (Cincotta A H et al, Exp Opin Invest Drugs, 1999, 10:1683). An aspect of this invention is a method of circumventing or attenuating this desensitization to dopamine D2 receptor agonist administration in the treatment of metabolic disorders. Endogenous dopamine release at appropriate levels appears to be less likely to induce these counter, desensitizing effects versus post-synaptic dopamine receptor stimulation with certain dopamine receptor agonists. Also, such endogenous dopamine is capable of binding to all post-synaptic dopamine receptors (D1, D2, D3, D4, D5) that can be more favorable versus dopamine receptor ligand binding to a single specific dopamine receptor site type (e.g., only D2). Understanding the nature of the involvement of dopaminergic neuronal activity within the central nervous system in regulation of metabolism will allow for the development of methods to better treat metabolic disorders. We have now discovered that increasing dopaminergic neuronal activity (as defined herein) produces a favorable influence on metabolic disorders. And, methods to circumvent or reduce desensitization, compensation and counteraction of dopamine receptor agonist administration that may under certain circumstances increase dopaminergic neuronal activity (namely avoiding dopamine D1 or D2 receptor agonist use or employing their use at low dosages that elicit either no or not better than modest [less than 50% of maximal response] metabolic responses) will improve the effectiveness of these methods to reduce metabolic disorders and make such approaches practical for long term use. For an example, it has now been found that it is possible to increase the effectiveness (benefit/adverse effect ratio) of dopamine D1 or D2 receptor agonists to reduce metabolic disorders by actually reducing the dose of these agents to ineffective levels and combining them with agents that increase synaptic dopamine level and/or agents that decrease norepinephrine neuronal activity (i.e, induction of synergism). That is, by directing treatment strategies for metabolic disorders towards increasing dopaminergic neuronal activity rather than towards dopamine agonist-dopamine receptor interaction per se, to effectuate a particular neurophysiology as defined herein, one can more effectively reduce metabolic disorders. Therefore any combination of dopamine receptor agonists and/or antagonists that ultimately results in an increase in dopaminergic neuronal activity can be used to reduce metabolic disorders and is in part the basis of this invention. Contrariwise, and equally importantly, use of any combination of dopamine receptor agonists and/or antagonists that ultimately does not result in an increase in dopaminergic neuronal activity cannot be used to effectively treat metabolic disorders. Specific methods to increase dopaminergic neuronal activity by utilizing specific dopamine receptor agonists and antagonists and other dopamine neuromodulators are described below. A key aspect of these said methods is to insure that synaptic dopamine levels are maintained or increased but never chronically reduced (whether said method involves administration of post-synaptic dopamine receptor agonists or not) to produce beneficial effects on metabolic disorders.
Similarly, norepinephrine ligand-binding functions produce a wide array of physiological responses depending upon which particular receptor site is bound and also depending upon which neuronal center is impacted. For example, pharmacological interventions that act to induce increases in central norepinephrine release and synaptic levels have been shown to stimulate weight loss and treat obesity, however increased central norepinephrine levels have been associated with obesity, insulin resistance and diabetes (Astrup A et al, Obesity, 2008, March 20:Epub; Gadde K M et al, Expert Rev Neurother, 2007, 7:17). Drugs that stimulate norepinephrine release or increase synaptic norpeinephrine level have been employed to treat obesity and have had limited success due to modest efficacy and adverse side-effects such as hyperactivity, hypertension, valvular heart disease, and increased heart rate (Ioannides-Demos L L et al, Drug Saf, 2006, 29:302; Florentin M et al, Obesity Rev, 2007, Nov. 23: Epub).
There are pharmaceutical agents that are classified as dopamine/norepinephrine reuptake inhibitors such as bupropion, mazindol, sibutramine, and methylphenidate to name but a few examples, that function to block the neuronal reuptake of synaptic dopamine and norepinpehrine and consequently increase both dopaminergic and noradrenergic neuronal activities (as defined herein—see below). These dopamine/norepinephrine reuptake inhibitors have been shown to produce beneficial effects on obesity and to some extent on diabetes as well. However, the effects of these dopamine/norepinephrine reuptake inhibitors are modest in all cases and are associated with untoward side-effects such as increased heart rate and hypertension. Likewise, agents that stimulate the concurrent neuronal release of dopamine and norepinephrine have produced modest positive yet very mixed results on obesity and diabetes and concurrent serious side effects. The untoward side effects of the dopamine/norepinephrine reuptake inhibitors and the dopamine/norepinephrine release enhancers also limit the dose that can be administered to the patient and consequently can limit the magnitude of any benefit on metabolic disorders as well. Contrariwise, the present invention provides an opposite method of treating metabolic disease from that of these dopamine/norpeinephrine reuptake inhibitors that employs approaches that counter-intuitively improve the effects of dopamine/norepinephrine reuptake inhibitors by actually inhibiting the effects of these agents. Methods of the present invention act to block the effects of increasing synaptic norepinephrine from these concurrent dopamine/norepinephrine reuptake inhibitor or pre-synaptic release stimulator agents and thereby improve metabolism. Such an approach also reduces the untoward side-effects of the dopamine/norepinephrine reuptake inhibitors or release enhancers. Likewise, dopamine beta hydroxylase inhibition has been shown to reduce norepinephrine levels and metabolic disorders, however, dopamine beta hydroxylase does not exist in dopamine neurons and therefore its inhibition cannot elicit any effect to increase dopaminergic neuronal activity and thereby produce a beneficial impact on metabolic disorders. What is needed to effectively treat metabolic disorders is a method that can increase central (central nervous system) dopaminergic neuronal activity and decrease central noradrenergic neuronal activity. We have now unexpectedly found that methods that increase dopaminergic neuronal activity and decrease norepinephrine neuronal activity interact and often synergize to reduce markedly and in sustained manner metabolic disorders and key elements thereof while minimizing adverse events.